EFFECT OF CORTISONE ON ACUTESTREPTOCOCCAL INFECTIONS AND POST-STREPTOCOCCAL COMPLICATIONS
Edward O. Hahn, … , Floyd W. Denny, Lewis W.Wannamaker
J Clin Invest. 1951;30(3):274-281. https://doi.org/10.1172/JCI102441.
Research Article
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EFFECT OF CORTISONEONACUTESTREPTOCOCCALINFEC-TIONS AND POST-STREPTOCOCCALCOMPLICATIONS1
BY EDWARD0. HAHN,2 HAROLDB. HOUSER,2CHARLESH. RAMMELKAMP,JR.,FLOYDW. DENNY,2 AND LEWIS W. WANNAMAKER2
(From the Streptococcal Disease Laboratory, Francis E. Warren Air Force Base, Wyoming, andthe Department of Preventive Medicine, Western Reserve University,
School of Medicine, Cleveland, Ohio)
(Submitted for publication November 22, 1950; accepted, December 11, 1950)
It has been established that adrenal hormonesplay an important role in the defense reaction ofthe body to stress (1). A common stress stimulusin man is that produced by infection with group Astreptococci. Streptococcal infections assumeespecial importance because they precede acuterheumatic fever, a disease which responds favor-ably to treatment with the adrenal hormone, corti-sone (2-4). An epidemic of streptococcal exu-dative tonsillitis and pharyngitis afforded theopportunity to obtain data on the effect of cortisonetherapy not only on an acute bacterial infection andthe immunological response of the host, but alsoon the subsequent occurrence of acute rheumaticfever.
DESCRIPTION OF STUDY
This study was conducted at Francis E. Warren AirForce Base, Wyoming, from February 20 to April 17,1950. All patients entering the hospital with respiratoryinfections were examinqd within a few hours after ad-mission. Since it was desirable to include in the studyonly those patients in the early phase of a streptococcalrespiratory infection who would be available for follow-up examinations, the following criteria were employed:(a) the presence of exudate on the pharynx or tonsils,(b) a total leucocyte of 10,000 or greater, (c) an illnesswhich began less than 31 hours before admission to thestudy, and (d) availability for follow-up studies for atleast four weeks.
One hundred and seventy-four patients fulfilled theabove criteria and were divided into treated and controlgroups on the basis of their Air Force serial number.Eighty-seven patients had numbers ending in the digits5-9 and received treatment; 87 with numbers ending inthe digits 0-4 received no specific therapy and composedthe control group.
Cortisone acetate was injected intramuscularly intothe gluteal region according to one of the two treatment
1This investigation was supported through the Com-mission on Acute Respiratory Diseases, Armed ForcesEpidemiological Board, Office of The Surgeon General,Washington, D. C.
2Capt. MC, AUS.
schedules. The first 17 patients received a total of 500mgms in 50 mgmdoses. The first injection was given atthe time of admission to the study and subsequent doseswere administered at 12 hour intervals. The remaining70 cases were given a total of 600 mgms in 100 mgmdoses. The initial injection was given at the time of ad-mission to the study, the second and third at 9 a.m. and9 p.m. on the second hospital day, and the remainingthree at 9 p.m. of the third, fourth and fifth days. Con-trol patients received 0.85 per cent sodium chloride in-jections by the same schedules. During hospitalization noantipyretics or other medications were given except co-deine for relief of severe headache.
Patients were examined daily through the sixth dayof illness by one member of the professional staff who hadno knowledge of the treatment being administered.Symptoms were recorded for each 12 hour period duringthe first two days of illness and daily thereafter. Physi-cal signs were recorded daily. Oral temperatures weretaken every four hours. Total leucocyte counts and cul-tures of the tonsils and pharynx were obtained each day.Sera were obtained on the first and sixth days of illness.An electrocardiogram was recorded soon after the acutesymptoms had subsided.
Subsequent examinations were conducted during thethird, fourth and fifth weeks following the onset- of thestreptococcal illness. The patients were questioned con-cerning post-streptococcal complications. Those withsymptoms were examined and admitted to the hospitalfor further study. An electrocardiogram was taken ap-proximately 21 days after onset. In addition, at each ofthe weekly examinations, serum and a culture of thethroat were obtained.
All cultures were examined for beta-hemolytic strepto-cocci which, when present, were isolated in pure culture.The first and last strains isolated during hospitalizationand all strains obtained at each subsequent examinationwere grouped and typed according to the methods ofMaxted (5, 6) and Swift, Wilson, and Lancefield (7).The acute and convalescent antistreptolysin "O" titers ofall sera from each patient were determined concomitantlyby a modification of the technique of Hodge and Swift(8).
RESULTS
That the patients in this study had streptococcaldisease is indicated by the demonstration of a sig-
274
EFFECT OF CORTISONEON STREPTOCOCCALINFECTIONS
nificant rise 8 in the antistreptolysin titer in the sera
of 86 per cent of the control group. In addition,group A streptococci were isolated from the initialcultures of the tonsils and pharynx of 89 per centof all patients and the symptoms and physical signswere characteristic of streptococcal infections (9).The data presented in Table I show that the twogroups of patients were essentially comparable.
The effect of cortisone on selected symptoms andphysical signs is presented in Figures 1 and 2.4Little or no effect on the acute illness was demon-strated. The symptom, sore throat, persistedsomewhat longer in the control group, being pres-
ent on the sixth day of observation in 20 per cent
TABLE I
Comparability of the 87 cases in each of the treatedand control groups
Cortisone Congroup goi
per
trol
up"XI
History of tonsillectomy 26.4 31.0Age 17-21 77.0 74.7Symptoms: *
Chilliness 65.5 75.8Feverishness 82.7 86.2Malaise 41.3 56.3Sore Throat 82.7 85.0Headache 86.2 80.4
Physical signs:tEnlarged or tender cervical nodes 91.8 90.8Lymphoid hyperplasia 37.9 37.9
Laboratory:Group A streptococci on admission 89.7 88.5
Type 14 54.0 65.5Type 24 17.2 10.3Type 6 9.1 9.1
Leucocyte count 12,000 or greater 91.9 86.2Antistreptolysin titer-125 units or
less on admission 68.9 67.8* Symptoms occurring during first 12 hours of illness.t Physical signs present on admission examination.
of the control patients and 6 per cent of the treatedcases. Chilliness, headache and malaise occurredwith equal frequency in the two groups. No dif-ference was noted between the treated and controlpatients in the time of disappearance of physicalsigns.
The number of patients with fever is recordedin Figure 3. At each four hour time period priorto treatment, the incidence of fever was the same
in the two groups. Following therapy, the per
8 A significant rise is considered to be two dilution in-crements when the convalescent titer is compared to theacute titer.
4 Observations made after the development of purulentcomplications in four patients from the control groupwere not included in this analysis.
0 1 2 3 4 5 6 1 2 3 4 5 6DAY OF DISEASE
FIG. 1. EFFECT OF CORTISONE THERAPYON THE SYMP-TOMSOF STREPTOCOCCALTONSILLITIS ANiD PHARYNGITIS
cent of patients with fever was greater in thosewho received cortisone than in the control group.
This difference, evident up to the third day oftreatment, was as great as 26 per cent.
There were 15 patients who developed a com-
plication during the period of treatment with corti-sone or saline injections (Table II). Two of the
c
zw
.7
Z 4z
w3w2CL
EFFECT OF CORTISONEON THE PHYSICALSIGNS OF STREPTOCOCCALSORETHROAT
ENLARGED EXUDATEDO-- CERVICAL 0-Xo ControlO-! NODES "4CortiSone
FI.I
0o /
10
:0
0 12 34 56 123 4 56DAYOF DISEASE
FIG. 2
275
E. HAHN, H. HOUSER, C. RAMMELKAMP,JR., F. DENNY, AND L. WANNAMAKER
TABLE II
The effect of cortisone on the constreptococcal sore thro
Coa_ -cg
Complication
Suppurative:A. During treatment
1. Peritonsillar cellulitis2. Otitis media3. Appendicitis
B. Following treatment1. Exudative tonsillitis2. Peritonsillar cellulitis3. Otitis media
Non-suppurative:Rheumatic fever
(87
three peritonsillar abscesses requdrainage, and in one instance ofspontaneous rupture occurred.patients from the control group Xas therapy. Symptoms of otitisent in six untreated and four trcwere not severe enough to requirIn the group treated with cortideveloped acute appendicitis, twhich began 20 hours after theWith continued administrationdominal tenderness and rigidity,rate, and an elevated leucocyte cooperation, 20 hours after the orsymptoms, a gangrenous appencNo beta-hemolytic streptococci Mcultures of the appendix takenoperation.
Suppurative complications, wdent within ten days after the Iobservation, occurred in six paticgroup and in five in the contrcgroup receiving cortisone four parences of exudative tonsillitis, onlar cellulitis and one with acutereadmitted to the hospital. In tthere were readmissions for exin three cases and peritonsillarpatients.
A total of seven patients dsuppurative sequela diagnosedmatic fever according to a mocthe classification of Jones (11).tients with rheumatic fever hadand five had received no theraptients exhibited migrating polyaran elevated sedimentation rate.
rheumatic fever was obtained in only one patientnplications of who was from the control group. The electro-
ratisone Control cardiographic abnormalities are recorded in TableIrtsone Controlroup group III. The interval from the onset of the observedcases) (87 cases)
respiratory infection to the first symptom of rheu-matic fever was 18 and 27 days in the treated
4 7 group and 13, 19, 19, 27 and 28 days in the control1 0 patients. None of the seven patients showed bac-4 3 teriological evidence of an intervening streptococcal
2 infection, although one patient from the control2 group (interval 13 days) entered the hospital with
peritonsillar cellulitis four days before the first
iired incision and symptom of rheumatic fever.acute otitis media There were 15 patients who exhibited abnor-All three of these malities of the P-R interval on the electrocardio-received penicillin gram recorded about 21 days after the onset ofmedia were pres- exudative tonsillitis or pharyngitis (Table III).eated patients but Of the patients who received cortisone the P-Re specific therapy. interval was greater than 0.21 seconds in five, andsone, one patient only one of these had symptoms of rheumatic fever.
he symptoms of In the control group of patients four showed a
initial injection prolongation of the P-R interval, three of whomof cortisone, ab- had symptoms of rheumatic fever. In addition,increase in pulse there were three patients in the treated and three
unt persisted. At patients in the control group whose P-R intervaluset of abdominal increased at least 0.04 second on the 21st day as
lix was removed, compared to the initial recording.vere isolated from Of the group of eight patients who showed ab-
at the time of normal P-R intervals on the electrocardiogramand who showed no other evidence of rheumatic
hich became evi- fever, four in the cortisone treated group showedperiod of hospital bacteriological evidence of a new infection. A new
ants in the treated type of streptococcus was isolated from the phar-fiv..'. U.%. %.1-.&.5 .v.
)I group. In theLtients with recur-ie with peritonsil-otitis media werethe control group,;udative tonsillitis
cellulitis in two
leveloped a non-as definite rheu-lification (10) of
Two of the pa-received cortisoney. All seven pa-rthritis, fever, andA past history of
TABLE III
Effect of cortisone therapy of acute streptococcal infections onthe post-streptococcal electrocardiogram
Cortisone Controlgroup group
ClassificationTotal Cases Total Casescases cases
Rheumatic fever: 2 5P-R interval greater than 0.21
second 1 3Increase P-R interval of at least
0.04 second* 1 2No symptoms of rheumatic fever: 85 82
P-R interval greater than 0.21second 4 1
Increase in P-R of at least 0.04second* 2 1
Totals 87 8 87 7
* Exclusive of individualsover 0.21 second.
showing a P-R interval of
276
EFFECT OF CORTISONEON STREPTOCOCCALINFECTIONS
ynx of three patients at the time of the secondelectrocardiogram but there was no other evidenceof infection. In one patient a new type of strepto-coccus was isolated at the time of readmission tothe hospital for exudative tonsillitis seven daysafter the onset of the original infection.
Total leucocyte counts were obtained daily dur-ing hospitalization in 96.6 per cent of the cases.The percentage of leucocyte counts greater than10,000 is recorded in Table IV according to hos-pital day. The number of elevated leucocytecounts fell continuously in the control group. Incontrast, the treated group showed a decrease inelevated counts on the second day followed by areturn to a high level and then a gradual fall.
Group A streptococci were isolated at some timeduring hospitalization in 95.3 per cent of thecortisone treated group and 96.5 per cent of thecontrol group. The same type of organism was
TABLE IV
Effect of cortisone therapy in streptococcal sore throat onthe total leucocyte count
Per cent of leucocyte counts greater than10,000 according to hospital day
Group
1 2 3 4 5
Cortisone 95.1 78.7 90.7 83.5 78.8Control 92.9 83.5 54.7 48.2 48.1
isolated during the acute illness and throughoutthe follow-up period in 79.5 per cent of the treatedgroup and 71.6 per cent of the untreated group.
A new type of streptococcus was identified in 8.5per cent of the cortisone group and 4.9 per centof the control group. All of these changes intype, except for one instance in the control group,
were demonstrated after discharge from thehospital.
The antistreptolysin titers of the sera collectedon admission to the hospital and five to seven daysafter the onset of the disease are recorded in Fig-ure 4. Since the distribution of the antistrepto-lysin titers of the acute phase sera is very similarin the two the average rise in the antibody titerduring convalescence may be compared.
At the end of the first week of illness the sera
of the control group showed an average rise of0.770 dilutions (Table V) as compared to a riseof 0.541 in the cortisone treated patients. During
Le EFFECT OF CORTISONEON THE OCCURRENCEOF FEVER0
MBEFORE AFTER THERAPY.* Cortisone treOt-
s^90]_= 00A-0Somntet
2 o7203-86 7 08
60 ¼-40~~~~~~I-0
U.~~~~~FG3pw
2012214 3648 60 72 8088
HOURS
FIG. 3
the subsequent three weeks the average increasein antibody was somewhat greater in the treatedgroup than in the patients who received no therapy.These differences were 0.175, 0.181, and 0.332dilution increments at the second, third and fourthweeks, respectively.5
6 In the,treated series, those patients who gave a historyof tonsillectomy had a higher antistreptolysin responsethan those with no such history. The average dilutionincrement in those without tonsils at the end of two, threeand four weeks was 4.454, 5.173, and 5.173, respectively,as compared to 3.350, 3.650, and 3.542 in the patients withtonsils. No difference was noted in the control group.
400317250200159125
8a3gg 62S5F 50
i=<50'
., 317P 25c2 20c
159125100
6Z550
<50
THE .EFFECT OF CORTISONEON THE ANTISTREPTOLYSIN
TITER IN STREPTOCOCCALSORE THROAT
CONTROL 2 1 41 22 1 64 4 I 9
162 I 105 10 1 17
27 2I1 I
7 ,~~~~~~~~2
CORTI6SAYOITE
FlG. 47 IG.14
277
E. HAHN, H. HOUSER, C. RAMMELKAMP,JR., F. DENNY, AND L. WANNAMAKER
TABLE V
The effect of cortisone on the antistreptolysin titer*
AverageDays after Number dilution
Group onset of of increase inillness sera antistrepto-
lysin titert
Cortisone 84 0.541Control - 84 0.770
Cortisone 79 3.607Control 14-18 81 3.432
Cortisone 2025 78 4.012Control 83 3.831
Cortisone 27-32 75 3.973Control 78 3.641
* The three patients who received penicillin therapy areexcluded.
t The initial dilutions of sera employed in the tests arerecorded in Figure 4. Each change in titer of one dilutionis assigned a value of one (plus or minus). All changes intiter are related back to the titer of the serum specimenobtained during the first 31 hours of illness.
The only untoward effect noted during cortisonetherapy was soreness around the area of injectionin all patients. The soreness was most markedduring the first 48 hours of therapy and dimin-ished somewhat by the time of the last injection.
DISCUSSION
Adrenocorticotrophic hormone (ACTH) andadrenal cortical extracts have been used in studiesdesigned to determine the effect of these hormoneson acute bacterial infections. Perla and Marmor-ston (12) treated 17 cases of bronchopneumonia,one case of induced malaria, and six severe "grip-pal" infections with adrenal cortical extract.These authors report that such therapy wasbeneficial in that it shortened the convalescentperiod. Jacobs (13) treated non-immunizedchildren who had whooping cough with adrenalcortical extract and reported the mildest coursein this group when compared to other similargroups receiving pertussis antigens or triple ty-phoid vaccine. More recently, Finland, Kass,and Ingbar (14) used ACTH in the treatmentof one case of pneumococcal pneumonia and onepatient with virus pneumonia. These patientsshowed rapid symptomatic improvement.
In contrast to the above studies, the data pre-sented here show that the adrenal hormone, corti-sone, in the doses used, had no effect on the symp-
toms or physical signs of acute streptococcal sorethroat. Furthermore, fever appeared to be pro-longed in those patients receiving cortisone.
Whether cortisone therapy affects the develop-ment of complications can not be determined fromthe data obtained. There were ten such complica-tions which developed in the control group duringthe period of treatment with saline and five in thecortisone treated group. There was one patienttreated with cortisone who exhibited abdominaltenderness and rigidity, rapid pulse rate, fever andleucocytosis. This is in contrast to the report ofBeck, Browne, Johnson, Kennedy and Macken-zie ( 15) who observed two patients who developedperitonitis during treatment with ACTHbut whofailed to exhibit the classical features of thisdisease.
Leucocytosis during the course of cortisonetherapy as demonstrated in this study has beennoted previously (16-19). The decrease in per-centage of treated patients having leucocyte countsgreater than 10,000 on the second day (Table IV)can possibly be explained by the fact that on thisday most of the determinations were made aboutone hour after treatment. This drop in total leu-cocyte count immediately following the injectionof ACTHand adrenal cortical extracts has beendescribed (1, 20, 21). The remaining counts weretaken about 13 hours following the previousinjection.
A number of investigators have studied the re-lationship between adrenal hormones (22-30) andantibody production. Chase, White, and Dough-erty (22) report that the administration of adrenalcortical extracts to animals receiving injectionsof staphylococcal toxin, horse serum, egg albuminor sheep cells results in higher antibody titers thanobtained in control animals which received noadrenal extract. Mirick (23), however, reportsthat in man the administration of ACTHor corti-sone does not alter the antibody response to im-munization with pneumococcal polysaccharides.Finland, Kass, and Ingbar (14) observed that inone patient with pneumococcal pneumonia treatedwith ACTHantibodies appeared in the serum atabout the expected time.
In contrast to the above reports, Fischel (24)demonstrated an inhibition of antibody formationin rabbits given ACTHduring immunization with
278
EFFECT OF CORTISONEON STREPTOCOCCALINFECTIONS
formalinized pneumococci. Germuth and Ottinger(25) report that ACTH and cortisone adminis-tration markedly suppressed the formation of anti-body to egg albumin in rabbits. In these experi-ments 10 mgms of cortisone were administereddaily for 18 days to rabbits weighing 2 kgms.Such therapy completely inhibited antibody forma-.tion to egg albumin. It is to be noted, however,that antibody was not measured several weeks af-ter the experimental period was completed. Therelative doses of cortisone employed in theserabbits were greater than those used in the presentstudy.
Antibodies to various products of group A strep-tococci are especially high in patients with rheu-matic fever (31, 32). Recently it has been dem-onstrated that the attack rate of rheumatic feverfollowing streptococcal pharyngitis is related, inpart, to the magnitude of the antibody response(33). Procedures which alter this antibody re-sponse may also alter the incidence of subsequentrheumatic fever. Thus penicillin therapy of acutestreptococcal pharyngitis inhibits the formation ofantibody presumably because of the eradicationof the antigen (streptococci) from the throat andat the same time such treatment markedly de-creases the incidence of acute rheumatic fever(10).
Cortisone therapy as employed in the presentstudy failed to alter appreciably the antistreptolysinresponse to streptococcal infections. Because thesera of the treated group showed a somewhat lowerantibody titer at six days than the sera of the con-trol group there may have been a slight inhibitionof antibody formation. It should be emphasized,however, that the increase in antibody was some-what greater in the treated group than in the con-trol patients two, three and four weeks after theonset of illness. This may be due to the fact thatcortisone is not antibacterial, so that when treat-ment was discontinued the antigenic stimulus wasstill effective.
The effect of cortisone therapy on acute strep-tococcal infections is of especial interest not onlybecause of the above considerations, but also be-cause the compound also exerts a remarkable ef-fect when administered to patients with rheu-matic fever (2-4). Acute rheumatic fever wasnot prevented by cortisone therapy. Although
there were only two cases in the treated group andfive cases among the control patients, this distri-bution could have occurred by chance. Since theincidence of abnormal electrocardiograms wasequal in the treated and control group of patients,cortisone therapy had no effect on these signswhich are frequently associated with rheumaticfever. Since there may have been a slight inhibi-tion of antibody formation during the period oftherapy, it is entirely possible that larger dosesof cortisone administered for a longer period oftime may inhibit antibody production and reducethe incidence of rheumatic fever.
SUMMARY
Eighty-seven treated and 87 control patientswere studied to determine the effect of cortisoneon the clinical and immunological response tostreptococcal respiratory infections. Cortisonetherapy, in the dosages employed, exerted no ef-fect on the symptoms or physical signs of thisinfection. Patients who received cortisone ex-hibited fever for a longer period of time than thecontrol patients. Suppurative complications de-veloped during the period of cortisone or salineinjections in one of the treated patients and in threeof the control subjects.
Rheumatic fever was diagnosed in two treatedand five control subjects. The P-R interval re-corded approximately three weeks after the onsetof illness was greater than 0.21 second in a totalof five of the treated and four of the control group.
The increase in the antistreptolysin titer wassomewhat less in the sera of the treated group thanin the control patients one week after the onsetof the infection, but at two, three and four weeksthe formation of antibody was slightly greater intreated than in the control patients.
ACKNOWLEDGMENTS
To Col. John K. Cullen and Col. Howard F. Currie,Post Surgeons, and Capt. James G. Hirsch, chief ofMedical Service, we express our deep appreciation, forwithout their cooperation this study would have beenimpossible.
We are pleased to acknowledge the assistance of thelaboratory staff: Mary E. Riner, technician in chief,Donna Carpenter, Joanne Merrill, Emily K. Lambert,Phyllis Guthrie, Elaine Jessen, John Datillo, T/Sgt.
279
280 E. HAHN, H. HOUSER, C. RAMMELKAMP,JR., F. DENNY, AND L. WANNAMAKER
Earl C. Marple, Sgt. Joe Page, Sgt. Frederick N. Bark-man, and Pfc. Ray F. Long.
Wealso wish to thank the following ward personnel fortheir admirable performance of ward duties far in excessof the usual load: Sgt. Charles W. Sass, Cpl. Norris E.Dieble, Cpl. Melvin L. Wood, Cpl. Johr. W. Roberts, andPfc. Alberto J. Romero.
REFERENCES
1. Selye, H., The general adaptation syndrome and thediseases of adaptation. J. Clin. Endocrinol., 1946,6, 117.
2. McEwen, C., Bunim, J. J., Baldwin, J. S., Kuttner,A. G. Appel, S. B., and Kaltman, A. J., The effectof cortisone and ACTH on rheumatic fever.Bull. N. Y. Acad. Med., 1950, 26, 212.
3. Hench, P. S., Kendall, E. C., Slocumb, C. H., andPolley, H. F., Effects of cortisone acetate andpituitary ACTH on rheumatoid arthritis, rheu-matic fever and certain other conditions. Arch.Int. Med., 1950, 85, 545.
4. Massell, B. F., The effect of ACTH on rheumaticfever and rheumatic carditis. Bull. New EnglandMed. Center, 1950, 12, 22.
5. Maxted, W. R., Preparation of streptococcal extractsfor Lancefield grouping. Lancet, 1948, 2, 255.
6. Wannamaker, L. W., Denny, F. W., Rammelkamp,C. H., Jr., and Brink, W. R., Use of Maxted'smethod for group classification of hemolytic strep-tococci. Proc. Soc. Exper. Biol. & Med., 1950, 73,467.
7. Swift, H. F., Wilson, A. T., and Lancefield, R. C.,Typing group A hemolytic streptococci by M pre-cipitin reactions in capillary pipettes. J. Exper.Med., 1943, 78, 127.
8. Hodge, B. E., and Swift, H. F., Varying hemolyticand constant combining capacity of streptolysins;influence on testing for antistreptolysins. J. Exper.Med., 1933, 58, 277.
9. Brink, W. R., Rammelkamp, C. H., Denny, F. W.,and Wannamaker, L. W., Effect of penicillin andaureomycin on the natural course of streptococcaltonsillitis and pharyngitis. Am. J. Med. (in press).
10. Denny, F. W., Wannamaker, L. W., Brink, W. R.,Rammelkamp, C. H., Jr., and Custer, E. A., Pre-vention of rheumatic fever. Treatment of the pre-ceding streptococcic infection. J. A. M. A., 1950,143, 151.
11. Jones, T. D., The diagnosis of rheumatic fever.J. A. M. A., 1944, 126, 481.
12. Perla, D., and Marmorston, J., Suprarenal corticalhormone and salt in the treatment of pneumoniaand other severe infections. Endocrinology, 1940,27, 367.
13. Jacobs, L., The treatment of pertussis with vaccinesand adrenal cortex extract. Arch. Pediat., 1943,60, 313.
14. Finland, M., Kass, E. H., and Ingbar, S. H., Effectsof ACTH in primary atypical (viral) pneumonia
and in pneumococcal pneumonia (preliminary re-port), in Proceedings of the First Clinical ACTHConference, edited by Mote, J. R. Blakiston Co.,Philadelphia, 1950, p. 529.
15. Beck, J. C., Browne, J. S. L., Johnson, L. G., Ken-nedy, B. J., and Mackenzie, D. W., Occurrence ofperitonitis during ACTH administration. Canad.M. A. J., 1950, 62, 423.
16. Thorn, G. W., Forsham, P. H., Frawley, T. F., Hill,S. R., Jr., Roche, M., Staehelin, D., and Wilson,D. L., The clinical usefulness of ACTHand corti-sone. New England J. Med., 1950, 242, 783.
17. Recant, L., Hume, D. M., Forsham, P. H., and Thorn,G. W., Studies on the effect of epinephrine on thepituitary-adrenocortical system. J. Clin. Endo-crinol., 1950, 10, 187.
18. Perera, G. A., Pines, K. L., Hamilton, H. B., andVislocky, K., Clinical and metabolic study of 11-dehydro-17-hydroxy-corticosterone acetate (Ken-dall Compound E) in hypertension, Addison's dis-ease and diabetes mellitus. Am. J. Med., 1949, 7,56.
19. Perera, G. A., Pines, K. L., Hamilton, H. B., andVislocky, K., Clinical study of 11-dehydro-17-hydroxy-corticosterone in hypertension, Addison'sdisease and diabetes. J. Clin. Invest., 1949, 28, 803.
20. Herbert, P. H., and deVries, J. A., The administra-tion of adrenocorticotrophic hormone to normalhuman subjects. The effect of the leucocytes inthe blood and on circulating antibody levels. En-docrinology, 1949, 44, 259.
21. Shapiro, A. B., and Schechtman, A. M., Effect ofadrenal cortical extract on the blood picture andserum proteins of the fowl. Proc. Soc. Exper.Biol. & Med., 1949, 70, 440.
22. Chase, J. H., White, A., and Dougherty, T. F., Theenhancement of circulating antibody concentra-tion by adrenal cortical hormones. J. Immunol.,1946, 52, 101.
23. Mirick, G. S., The effect of adrenocorticotrophic hor-mone and cortisone on antibody production in hu-man beings. J. Clin. Invest., 1950, 29, 836.
24. Fischel, E. E., The relationship of adrenal corticalactivity to immune responses. Bull. N. Y. Acad.Med., 1950, 26, 255.
25. Germuth, F. G., Jr., and Ottinger, B., Effect- of 17-hydroxy-1l-dehydrocorticosterone (compound E)and of ACTH on Arthus reaction and antibodyformation in the rabbit. Proc. Soc. Exper. Biol. &Med., 1950, 74, 815.
26. Houghton, B. C., Thatcher, J. S., and Hilles, C., Therole of the adrenal gland in immune mechanisms.J. Lab. & Clin. Med., 1947, 32, 1410; also CentralSoc. Clin. Research, 1947, 20, 20.
27. Thatcher, J. S., Houghton, B. C., and Ziegler, C. H.,Effect of adrenalectomy and adrenal cortical hor-mone upon the formation of antibodies. Endo-crinology, 1948, 43, 440.
28. Eisen, H. N., Mayer, M. M., Moore, D. H., Tarr,
EFFECT OF CORTISONEON STREPTOCOCCALINFECTIONS
R. R., and Stoerk, H. C., Failure of adrenal corticalactivity to influence circulating antibodies andgamma globulin. Proc. Soc. Exper. Biol. & Med.,1947, 65, 301.
29. Roberts, S., and White, A., Influence of adrenal cor-tex on antibody production in vitro. FederationProc., 1950, 9, 220.
30. Bjorneboe, M., Serum proteins during immunization.Acta path. et microbiol. Scandinav., 1943, 20, 221.
31. Rothbard, S., Watson, R. F., Swift, H. F., and Wilson,A. T., Bacteriologic and immunologic studies on
patients with hemolytic streptococcic infectionsas related to rheumatic fever. Arch. Int. Med.,1948, 82, 229.
32. Rantz, L. A., Randall, E., and Rantz, H. H., Anti-streptolysin "O"; a study of this antibody in healthand in hemolytic streptococcus respiratory diseasein man. Am. J. Med., 1948, 5, 3.
33. Denny, F. W., Wannamaker, L. W., and Rammel-kamp, C. H., The relationship of antibody produc-tion to the development of rheumatic fever (to bepublished).
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